2020A Question 13
Describe the time course between an intravenous injection of a general anaesthetic agent to loss of consciousness. Explain the delay using pharmacokinetic principles.
Examiner Report
The question had two parts, one asking about the time course between an intravenous injection of anaesthetic agent to loss of consciousness, the other asking to use pharmacokinetic principles.
The domains covered were the concept of the effect site and determining ke0, factors which contribute to the change in plasma concentration over time, diffusion and to a lesser extent effect site changes that result in loss of consciousness (e.g receptor binding, activation and change of resting membrane potential).
Many candidates simply stated Fick’s Law of diffusion and discussed the factors responsible for a drug moving across a plasma membrane with no mention of pharmacokinetic principles. A description of the role of the effect site equilibration rate constant (ke0) and equilibrium half-life (t1/2ke0) in the delay in onset was expected. Candidates mentioned ke0 with a brief definition but very few were able to give explanations about what drug factor altered the constant or how differing intravenous agents differ in their equilibrium half-life that lead to different onset times. Those who could, generally did very well. Discussions about absorption were superfluous for an intravenous agent. Likewise lengthy discussions about metabolism when discussing time to loss of consciousness were unnecessary.
A good reference is provided in: Pharmacology and physiology for Anesthesia. Hemmings and Egan. Chapter 2
Model Answer
Structure:
- Introduction
- Kinetics/dynamics
- Dynamics
- Special populations
Introduction
| Term | Detail |
|---|---|
| IV induction agent | - Induces LOC in one arm-brain circulation time (30sec in adult) - Propofol: 1-2mg.kg-1 - Thiopentone: 3-7mg.kg-1 - Ketamine: 1-2mg.kg-1 - Etomidate: 0.3mg.kg-1 - Midazolam: 0.3mg.kg-1 |
| Problems | - Three compartment model poorly describes induction kinetics - Variable relationship between dose and concentration (= kinetics) - Variable relationship between concentration and effect (= dynamics) |
| Implications | - Risk of overdose → Hypotension - Risk of underdose → Risk of awareness - Propofol TCI models are inaccurate at induction |
Kinetics
| Property | Detail |
|---|---|
| Time course | - Kinetics = administration → Plasma concentration (Cp) - Three compartment model inaccurate - Mostly patient-dependent delay - Biophasics = plasma concentration → Effect site concentration (Ce) - Represented by t1/2ke0 - Inferred from lag between ∆Cp and ∆EEG pattern - Mostly drug-dependent delay |
| Determinants | Speed of LOC ∝ (magnitude of peak effect) / (time to peak effect) (A) Magnitude of peak effect ∝ - ↑ Dose size - ↑ Speed of injection (bolus cf. TCI injection) - ↓ Cardiac output (↑ pregnant/neonate/obese, ↓ elderly/shock) - ↓ Central blood volume (↑ pregnant/obese/neonate, ↓ elderly/shock) - ↑ Speed and extent of recirculatory second peak (important if bolus is slow) (B) Time to peak effect ∝ - ↑ Rate of delivery to effect site - ↑ Cardiac output (note bivalent effects) - ↓ Distance from injection site to brain (e.g. CVC cf. lower limb PIVC) - ↑ Rate of effect site equilibration (↑ ke0 → ↓ T1/2ke0) ! - ↓ Thickness (e.g. Immature BBB in neonate) - ↑ Lipid solubility (e.g. Thiopentone: T1/2ke0 1 min → Clear endpoint) - ↑ % Unionized (e.g. Propofol >99%: T1/2ke0 2.6 mins) |
Dynamics
| Property | Detail |
|---|---|
| Time course | - Dynamics = effect site concentration → Effect - Represented by dose response curve - Effect on brainstem, thalamus, cerebral cortex - Bind receptor → Activate receptor → Ion flux → ↓ Membrane potential → ↓ Electrical activity → LOC - Minimal delay |
| Physiology | - Neonate: Immature brain structures and pathways → ↓ Cp50 - Elderly: ?↓ ion channel function, ?↓ synaptic activity - Pregnancy: Progesterone → ↓ Cp50 - Obesity: Inflammatory cytokines → ↓ Cp50 |
| Pathology | ↓ Cp50 if: - ↓ MAP (≤40mmHg) - ↓ PO2 (≤40mmHg) - ↑ PCO2 (>60mmHg sedation, >80mmHg anaesthesia if acute) - ↓ Temp - ↓ PH ↑ Cp50 if: - Anxiety, ↑ SNS - ↑ Temp |
| Drug interaction | - Synergistic: E.g. Fentanyl 1μg/kg reduces dose of propofol by 20% - Additive: E.g. ↓ propofol Cp50 if co-induction with volatile agent - Infra-additive: E.g. Ketamine + midazolam - Antagonistic: E.g. Propofol + acute amphetamines - Tolerance: Chronic barbiturate use → ↑ Cp50 |
| Pharmacogenomics | - e.g. Propofol Cp50 for immobility is 15μg.mL-1 with std dev 5μg.mL-1 - Polymorphism of receptors, ion channels, ICF signalling |
Special Populations
| Changes | Time to peak | Magnitude of peak | |
|---|---|---|---|
| Neonate | ↑ CO +100% ↑ %CO to brain ↓ Arm-brain distance |
↓ | ↓ |
| Pregnant | ↑ CO +25% ↓ %CO to brain ↑ BV 50% |
↓ | ↓ |
| Elderly | ↓ CO variable ↓ BV variable ↑ %CO to brain variable |
↑ | ↑ |
| Shocked | ↓ CO ↓ BV ↑ %CO to brain |
↑ | ↑ |